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Regulatory Requirements


... Vulnerability of the study population * Trial Conduct Data Evalution and Writing of Clinical Trial Report Trial Design and Trial Initiation Regulatory ... – PowerPoint PPT presentation

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Title: Regulatory Requirements

Regulatory Requirements
  • DIA, Clinical Forum, Dublin, 7 October 2013
  • Fergus Sweeney, Head, Inspections and Human
    Medicines Pharmacovigilance
  • , European Medicines Agency

  • The views presented in this presentation/these
    slides are those of the author and should not be
    understood or quoted as being made on behalf of
    the EMA and/or its scientific committees

Regulatory Requirements and guidelines for
quality of design
  • Directive 2001/83/EC Annex 1
  • Directive 2001/20/EC and directive 2005/28/EC
  • General guidelines GCP, Statistical analysis,
    Clinical study report, Clinical trials in
    paediatric or elderly populations
  • Guidelines on clinical development of medicinal
    products in specific therapeutic areas
  • Scientific advice (non-binding) optional
    possibility for sponsor to seek scientific advice
    on the development of a medicine - clinical,
    pre-clinical, pharmaceutical

Regulatory requirements for clinical trial design
  • Legislation is general broad principles.
  • More information is in guidance but it still
    offers considerable flexibility.
  • Guidance leaves much to be defined by the sponsor
    in their policies, processes and procedures.
    Better alternatives can be justified case by
  • The detail or complexity of trial conduct is
    driven by established practice, perceived
    requirements, the oral and written culture
    which is very open to change. Many of the issues
    lie in this cultural category as do the
    obstacles to change.

Defining Quality
  • Quality sufficient to support the decision making
    process on medicines throughout the clinical
    development and use post-marketing authorisation
  • Collecting data, generating information, enabling
    decision making by
  • Sponsors
  • Ethics Committees
  • Regulators
  • Investigators
  • Healthcare professionals
  • Study subjects
  • Patients
  • Ensuring
  • Subject rights, safety and welfare
  • Robustness of data

  • Current Developments

Current developments helping to make that
flexibility clear and put into practice
  • EU GCP IWG/CTFG draft Reflection paper on risk
    based quality management publication soon
  • OECD Recommendation on risk based approach
    endorsed final recommendation published 10 Dec
  • FDA Guidance for Industry on Risk based
    approaches to monitoring published August 2013
  • EU GCP IWG / CHMP Points to consider on GCP
    inspection findings and the benefit-risk balance
    Final publication in coming weeks
  • EU Draft regulation on clinical trials

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Points to consider on GCP inspection findings
and the benefit-risk balance
  • Agreed by GCP IWG, adopted by CHMP November 2012.
  • It is a Discussion paper on key GCP inspection
    issues impacting risk / benefit considerations by
  • Objective - to assist inspectors and assessors in
    evaluating the consequences of inspection
    findings in relation to the benefit-risk balance.
    Building prioritisation and risk assessment into
    conclusions and decisions based on inspection.
  • Three categories are used
  • Inspection findings which are likely to influence
    the benefit-risk evaluation
  • Inspection findings which may influence the
    benefit-risk evaluation
  • Inspection findings which are less likely to
    influence the benefit-risk evaluation

  • Many non-compliances may result in increased
    variability/reduced precision
  • May blur real differences between treatment
  • For superiority studies , if superiority has been
    established, non-compliances which increase
    variability, but not introducing bias favouring
    one treatment over the other are relatively
  • For non-inferiority studies. Increased
    variability may disguise a real difference
    between products. On the other hand, increased
    variability tends to widen the confidence
    interval for the mean difference/ratio between
    the test and comparator making the
    non-inferiority claim more difficult to obtain.
  • Non-compliance in the intermediate and low-impact
    category may not affect the benefit-risk
    assessment looked upon in isolation.
  • Major ethical flaws have an impact on the final
    conclusions about approvability of an
    application. Consequently, ethical misconduct
    could result in rejection of the application.

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Final Version Agreed and published
  • Picture of new CT regulation

Draft regulation on clinical trials. for
co-decision by Council and Parliament
  • Single dossier, single application portal for EU,
    encompassing regulatory and ethics review.
  • Joint assessment of core information Part 1
    between involved member states and national
    assessment of Part 2. Single decision per trial
    and per member state.
  • Low intervention trials marketed product within
    SPC or established medical practice rapid
    assessment, dossier is simple, additional
    labeling only if required by study design.
  • Emergency treatment trials
  • Insurance, labeling
  • Improved framework for safety reporting

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  • Some data from inspection findings

GCP inspections requested by EMA 2000-2012
Monitoring findings
  • Critical 45
  • Major 145
  • Minor 87
  • Total 277

  • Based on verbatim finding only
  • Review of supporting evidence not yet included
  • Some items insufficient monitoring are further
    detailed in the report but not in the database
    need more investigation
  • Minor findings not reviewed

GCP inspections requested by EMA
2000-2012 Monitoring findings
Finding type Critical Major Total
Monitor did not report/act on problems 8 20 28
Deficient SDV 9 15 24
Insufficient Monitoring 5 34 39
No action by sponsor 7 10 17
Failure to visit lab or other technical facility 2 7 9
Failure to visit sub-investigator sites 3 4 7
Late to start, big gaps, not to plan 11 32 43
IMP related issues 0 17 17

  • If you dont have a monitoring plan
  • and even when you do it is not followed
  • and even when it is followed its feedback loop
    is not acted on
  • and key areas are omitted from the plan
  • Correct planning, design, priority setting and
    risk management would enable sponsors to
  • ensure staff focus on what matters,
  • be more effective,
  • deliver good data,
  • convince regulator that process is in control
  • and that the choice of priorities is correct
  • and risk mitigation appropriate.

  • Analysis of inspection findings on monitoring and
    of other key areas.
  • What are the issues for sponsors to improve?
  • What are the issues for regulators to improve?
  • Do they already have the correct emphasis?
  • What were the major regulatory impacts
    relationship between GCP non-compliance and
    marketing authorisation outcome?
  • Scientific advice is linked to better outcome at
    MA do sponsors who seek SA also fare better on

  • Thoughts for the day and for the future

Heisenberg uncertainty principle
  • uncertainty principle - mathematical inequalities
    asserting a fundamental limit to the precision
    with which certain pairs of physical properties
    of a particle can be known simultaneously (e.g.
    position and momentum).
  • observer effect the impact the act of observation
    has on a phenomenon being observed.
  • Querying, monitoring, auditing - by sponsors
  • Reviewing, questioning, inspecting by
  • All change behavior people change the way they
    work, organizations change emphasis and process
    based on these.
  • All these are usually addressed with emphasis on
    negative rather than positive aspects
  • Beware of unintended consequences

Quality in clinical trials
Data Evalution and Writing of Clinical Trial
Regulatory Submissions and/or Publications
Trial Design and Trial Initiation
Trial Conduct
  • Prioritization and risk mitigation approaches
    across several dimensions
  • Protection of trials subjects Rights, Safety,
  • Credibility of data and results
  • Stratified according to knowledge of product (MA
  • Medicine authorised in EU used within terms of MA
    or within established treatment regimen
  • Medicine authorised in EU used significantly
    outside of MA, Medicine without MA in EU
  • Customized approach depending on
  • Protocol complexity, extent of interventions
    related to trial
  • Therapeutic indication and nature of endpoints,
    including population and co-medications
  • Administration of the product, dose, formulation
  • Complexity of study procedures and measurement,
    including the nature of the intervention
  • Vulnerability of the study population

Clinical trial product lifecycle
NB The shape of the curves, crossover, etc. are
not based on specific data. This is purely
illustrative for discussion. Actual situation
will vary case by case.
  • Resource is finite
  • Money
  • Time time in the day to get things done short
    term and elapsed time over long term
  • If you are designing a trial and have 1,000,000
    to spend on it
  • . for each 50,000 you decide to spend on one
    thing . you have 50,000 less to spend on
    something else
  • .so each time you decide you cannot live
    without a particular set of data/monitoring
    process/electronic gadgetdecide what it is you
    are living without .because it wont get done.
  • Instead of just taking a risk, prioritise and

  • Prioritise
  • Design
  • Anticipate
  • Assess risks, accept or mitigate
  • Revise design
  • Implement
  • Train, Do, Check, Review, Adjust
  • Train, Do, Check, Review, Adjust
  • Dont just think of Corrective Action
  • implement with Preventive Action

  • Perfection is achieved, not when there is
    nothing more to add, but when there is nothing
    left to take away. ?
  • Antoine de Saint-Exupéry,

Thank you questions suggestions GCP_at_ema.europ